Contemporary Pharmacotherapeutics and the Management of Aggressive Behavior in an Adolescent Animal Model of Maladaptive Aggression

Abstract

Objective: Antipsychotic and anticonvulsant medications are increasingly being used as pharmacotherapeutic treatments for maladaptive aggression in youth, yet no information is available regarding whether these drugs exhibit aggressionspecific suppression in preclinical studies employing adolescent animal models of maladaptive aggression. This study examined whether the commonly used antipsychotics medications haloperidol and risperidone and the anticonvulsant medication valproate exert selective aggression-suppressing effects using a validated adolescent animal model of maladaptive aggression. Methods: Twenty-seven-day old Syrian hamsters (Mesocricetus auratus) were administered testosterone for 30 consecutive days during the first 4 weeks of adolescent development. The following day (during late adolescence), experimental animals received a single dose of haloperidol (0.00, 0.025, 0.50, 1.0 mg/kg), risperidone (0.00, 0.01, 0.03, 1.0 mg/kg), or valproate (0.00, 1.0, 5.0, 10.0 mg/kg) and tested for offensive aggression using the Resident/Intruder Paradigm. As a baseline, non-aggressive behavioral control, a separate set of pubertal hamsters was treated with sesame oil vehicle during the first 4 weeks of adolescence and then tested for aggression during late adolescence in parallel with the haloperidol, risperidone or valproate-treated experimental animals. Results: Risperidone and valproate selectively reduced the highly impulsive and intense maladaptive aggressive phenotype in a dose-dependent fashion. While haloperidol marginally reduced aggressive responding, its effects were non-specific as the decrease in aggression was concurrent with reductions in a several ancillary (non-aggressive) behaviors. Conclusion: These studies provide pre-clinical evidence that the contemporary pharmacotherapeutics risperidone and valproate exert specific aggression-suppressing effects in an adolescent animal model of maladaptive aggression.

Valproate selectively suppresses adolescent anabolic/androgenic steroid-induced aggressive behavior: implications for a role of hypothalamic γ-aminobutyric acid neural signaling

“…Behavioral data from our prior studies show that adolescent hamsters repeatedly exposed to moderate doses of AAS (5.0 mg/kg/day) display an intense aggressive phenotype in the absence of prior social interactions and established dominance cues (Grimes et al ., 2006; Melloni and Ricci, 2010; Melloni et al ., 2016). Recently, we made the case that the aggressive phenotype observed in adolescent AAS-treated hamsters shared many behavioral similarities with maladaptive or ‘pathological’ aggression observed in humans (Einberger et al ., 2020), a form of aggression that is characterized by frequent, intense and prolonged aggressive outbursts and behaviors. In clinical settings, pathological aggression has been historically treated with antipsychotic medications (Schur et al ., 2003; Findling et al ., 2005).…”

“…Consistent with our previous findings (Grimes et al ., 2006; Melloni and Ricci, 2010; Melloni et al ., 2016; Einberger et al ., 2020), behavioral data from the first experiment showed that pubertal hamsters administered AAS display a highly escalated aggressive phenotype stereotypic of pathologic aggression. Results from the second experiment showed that valproate could selectively suppress this highly intense form of aggressive responding in a dose-dependent manner.…”

“…Adolescent AAS use increases the risk for aggressive (Bahrke et al ., 1990; Su et al ., 1993; Kouri et al ., 1995; Pope Jr. et al ., 2000; Daly et al ., 2003; Pagonis et al, 2006a, 2006b) and antisocial behaviors (Kindlundh et al ., 1999; Lood et al ., 2012; Hallgren et al ., 2015), including bullying, criminality and conduct problems, with a high proportion of adolescent users, reportedly engaged in criminal activities such as weapons use, rape and violent crime (Skårberg et al ., 2010; Hallgren et al ., 2015). The aggressive phenotype observed in adolescent AAS users shares behavioral similarities with maladaptive or ‘pathological’ aggression in youth, including frequent intense and prolonged aggressive outbursts (Kessler et al ., 2006; Einberger et al ., 2020). The pharmacological management of pathological aggression in adolescent psychiatric settings has consisted primarily of typical and atypical antipsychotic medications (Connor et al ., 1998; Schur et al ., 2003; Findling et al ., 2005; Knapp et al ., 2012).…”

“…Over the past two decades, we have used pubertal Syrian hamsters ( Mesocricetus auratus ) as an adolescent animal model to examine the effect(s) of adolescent AAS use on the behavioral neurobiology of aggression (Melloni and Ricci, 2010; Morrison and Melloni, 2014; Melloni et al ., 2016). Behavioral findings from these studies show clearly that adolescent hamsters exposed to AAS display a highly intense form of aggressive responding characteristic of pathological aggression (Melloni et al ., 2016; Einberger et al ., 2020). In particular, adolescent AAS-treated animals exhibit frequent and prolonged bouts of targeted offensive attacks (a measure of high aggression intensity).…”

Prediction of Locomotor Activity by Infrared Motion Detector on Sleep-wake State in Mice

“…Animal studies are effective to explore the pathophysiology of mental disorders and to initially evaluate the efficacy of drugs that are difficult to perform in human studies [ 1 - 6 ]. Even though some animal studies have faced with difficulties to find proper animal models, animal research on sleep-wake cycles related to sleep disorders or circadian rhythm disorders could be beneficial due to the commonality of sleep-wake states between human and animal [ 7 ].…”